1. Field of the Invention
This invention relates to the use of certain substituted 4-aminopyrrole(3,2-d)pyrimidine derivatives which selectively bind to mammalian neuropeptide receptors. It further relates to the use of such compounds and compositions in treating feeding disorders and certain cardiovascular diseases.
2. Description of the Related Art
Neuropeptide Y, a peptide first isolated in 1982, is widely distributed in the central and peripheral neurons and is responsible for a multitude of biological effects in the brain and the periphery. Various animal studies have shown that activation of neuropeptide Y receptors is related to vasoconstriction, Wahlestedt et al. Regul. Peptides, 13: 307-318 (1986), McCauley and Wesffall, J. Pharmacol. Exp. Ther. 261:863-868 (1992), and Grundemar et al., Br. J. Pharmacol. 105:45-50 (1992); and to stimulation of consummatory behavior, Flood and Morley, Peptides, 10:963-966 (1989), Leibowitz and Alexander, Peptides, 12:1251-1260 (1991), and Stanley et al. Peptides, 13:581-587 (1992).
Grundemar and Hakanson. TIPS, May 1994 [Vol. 15], 153-159, state that, in animals, neuropeptide Y is a powerful stimulus of food intake, and an inducer of vasoconstriction leading to hypertension. They further point out that low levels of neuropeptide Y (NPY) are associated with loss of appetite. These reports clearly indicate that compounds that inhibit the activity of this protein will reduce hypertension and appetite in animals.
EPO759441 and U.S. Pat. No. 5,576,337 report that physiological disorders related to neuropeptide Y include:
disorders or diseases pertaining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure; PA1 conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, and operations and surgery in the gastrointestinal tract; cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia, and dementia; PA1 conditions related to pain or nociception; PA1 diseases related to abnormal gastrointestinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn's disease; PA1 abnormal drink and food intake disorders, such as anorexia, and metabolic disorders; PA1 diseases related to sexual dysfunction and reproductive disorders; PA1 conditions or disorders associated with inflammation; PA1 respiratory diseases, such as asthma and conditions related to asthma and brochoconstriction; and diseases related to abnormal hormone release, such as leutinizing hormone, growth hormone, insulin, and prolactin. PA1 diagnosis and treatment of feeding disorders such as obesity and bulimia; disorders or diseases pertaining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure; PA1 conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, and operations and surgery in the gastrointestinal tract; cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia, and dementia; PA1 conditions related to pain or nociception; PA1 diseases related to abnormal gastrointestinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn's disease; PA1 abnormal drink and food intake disorders, such as anorexia, and metabolic disorders; PA1 diseases related to sexual dysfunction and reproductive disorders; PA1 conditions or disorders associated with inflammation; PA1 respiratory diseases, such as asthma and conditions related to asthma and brochoconstriction; and diseases related to abnormal hormone release, such as leutinizing hormone, growth hormone, insulin, and prolactin.
WO 96/14307 describes substituted benzylamine derivatives which selectively bind to human neuropeptide Y1 receptors.
The synthesis of certain 4-aminopyrrole(3,2-d)pyridines is described in Pharm. Chem J. 22, 185 (1988); 8, 14 (1974); and 7, 19 (1973). These compounds were reported to have antibacterial and antitumor activity.